Tuberculosis (TB) kills 2 million people every year. Although most humans control Mtb infection and maintain it in a latent state, ~10% of infected people have active or reactivated TB. It is our hypothesis that the M. tuberculosis infection of the human host results in a mutually beneficial structure, the granuloma, and the balance of host and microbial factors within this microenvironment determines outcome of infection, during both primary tuberculosis and latent infection. The host effector mechanisms that are important in control of TB remain incompletely understood, and the modulation of these responses, as is necessary for a chronic infection to prevent overwhelming pathology, has only begun to be explored. In this application we will concentrate on a specific T cell subset believed to contribute to the control of Mtb infection, the CD8 T cells. We have been studying CD8 T cells in TB for several years, and many questions remain regarding priming, effector functions, regulation and memory responses of these cells. In this application, we will use both mouse and non-human primate models of TB to address specific aspects of CD8 T cells in TB. We hypothesize that CD8 T cell responses are less than optimal, and effector functions, which include cytokine production and cytotoxic activity, are modulated by regulatory mechanisms. Furthermore, the CD8 T cell memory response is not robust upon challenge, and we hypothesize that the inflammatory response in the lungs during early infection or challenge is insufficient to quickly prime or recall a CD8 T cell response. Cumulatively, these studies will enhance our understanding of the host-pathogen interactions within the granuloma, as well as highlight mechanisms that may prevent bacterial clearance, reduce pathology, or improve control of the infection. These studies have relevance to vaccine development, since several TB vaccines that are entering human trials appear not to induce CD8 T cell responses; the relative importance of these responses compared to other cellular responses is unknown. The specific aims for this renewal are: 1. Determine the important effector functions of CD8 T cells in tuberculosis, and identify factors that modulate changes in these functions over the course of infection 2. Identify factors that regulate CD8 T cell responses during the course of infection 3. Determine whether CD8 T cell memory is initiated, maintained and recalled in the setting of cured or latent tuberculosis, and the factors that contribute to the ineffective memory response.